Alterations in gene expression contribute to the adaptations of brain reward circuits that underlie persistent behaviors associated with drug abuse. Epigenetic regulation of transcription mediated by posttranslational modification of histone proteins is emerging as an important mechanism used by environmental factors, including drugs of abuse, to control gene expression. Identifying the histone modifying factors that respond to drugs of abuse and understanding how chromatin regulation affects behavior are crucial for making progress toward understanding the neural basis of drug addiction. One intriguing candidate for this process is the methyl-DNA binding transcriptional represser MeCP2 as this protein plays important roles in brain development and function. MeCP2 is known to repress its target genes by recruiting both histone deacetylase and methyltransferase enzymes. Interestingly, given the conservation between activity-dependent and drug-induced mechanisms of transcriptional regulation, we have recently found that MeCP2 is phosphorylated in an activity-dependent manner in neurons at a site that dynamically modulates the ability of MeCP2 to repress its target gene Bdnf. We hypothesize that MeCP2 is a key mediator of cocaine-regulated transcription, and that the regulation of repressive histone methylation contributes to the development of drug sensitization behaviors. We propose to test this hypothesis by combining biochemical analyses of cocaine-dependent regulation of MeCP2 and histone methylation with experimental manipulation of these processes in mouse models of drug abuse. Our specific aims are: 1) to examine the functional regulation of MeCP2 by drugs of abuse;2) to investigate the contribution of epigenetic transcriptional repression mechanisms to cocaine-regulated gene expression;and 3) to evaluate the contribution of epigenetic mechanisms of gene transcription to drug-induced behavioral sensitization. These studies will fill a critical gap in knowledge by defining new mechanisms that contribute to the effects of cocaine on both neuronal gene expression and behavior. The identification of epigenetic mechanisms involved in regulation of gene expression by drugs of abuse may reveal new targets for therapies in treatment of drug addiction.